Conventional operation of the spray dryers used in the pharmaceutical industry use solely the drying gas to dry and pneumatically transport the dried powder to a cyclone and/or filter bag [Masters, K. “Spray drying handbook.” (1991)]. Often the drying conditions required to obtain the desired attributes (e.g. density, particle size) restrict process throughput and/or lead to materials that have a higher than desirable solvent/water content which may pose a stability problem, particularly in the processing of amorphous solid dispersions. Also, the use of very high throughputs of feed solution often leads to condensation problems and accumulation of material on the walls of the equipment when spray drying high boiling point solvents such as water.
In spray dried dispersions (SDD) the active pharmaceutical ingredient (API) is molecularly dispersed in a polymeric matrix. The polymer is used to stabilize the amorphous and metastable form of the drug and also to sustain supersaturation of the API in solution/biological fluids, thereby increasing bioavailability. The inherent use of solvents in spray drying processes contributes to a plasticization effect and correspondent undesirable decrease of the glass transition temperature (Tg) of amorphous solid dispersions during the drying process. The Tg is one of the most important attributes of an amorphous solid dispersion since it can be intrinsically related with the API molecular mobility and is one of the characteristics that dictates whether a spray dried dispersion formulation is stable enough to prevent crystallization over the shelf-life of the product.
Typical operations downstream to the spray drying step in a pharmaceutical process include blending, roller compaction and tableting or capsule filling. The ability for a SDD material to flow and be processed in the downstream equipment with no major operational difficulties is closely related to powder properties, namely particle size, density and cohesive—adhesive forces balance between the ingredients and equipment. Rule-of-thumb strategies for improving flow indicate that both particle size and density should be as large as possible. On a best-case scenario, the powder would also have the necessary compressibility (indicated by the relation between bulk and tap density) to enable a direct compression approach.
The spray drying literature includes a number of examples where additional streams of fluids are added to the process train with the aim of reducing wall accumulation. For example, U.S. Pat. No. 5,596,817 discloses a process where product deposition is minimized by injection of high velocity and low flow rate gas in the top of the drying chamber and near the chamber walls, enabling an efficient sweeping effect. U.S. Pat. No. 3,895,994 also discloses a spray drying process where product deposits on the cylinder wall and their recirculation into the high temperature zone are minimized through the introduction of tangential gas streams from the inlets arranged around the discharge end of the cylinder of spray dryer so as to swirl within said cylinder. However, neither of these patents specifically discuss problems associated with spray drying to produce amorphous solid dispersions of active pharmaceutical ingredients and polymers. The additional gas streams in these patents are used simply to minimize solid deposits forming on the walls of the spray dryers, and not to provide enhanced powder properties.
The state-of-the-art also includes a number of examples where a modified spray dryer setup was used to optimize powder properties. For example, EP patent application 0387950 discloses a device for obtaining a spray-dried product of predetermined bulk density. The nozzle is surrounded by a tube supplying a gas with dry particulate material. The ratio and speed of collision between the gas-solid suspension and spray enables the control of powder bulk density. WO 2011/154014 discloses a spray drying process where the drying gas supplied to the chamber is enriched in one or more solvent vapors to adjust the properties of the particles, namely their density and solvent content.
U.S. Pat. No. 8,337,895 discloses a process mostly intended for inhalation products that comprises a conditioning zone with controlled humidity and temperature to modulate droplet drying and promote surface enrichment of the active components, and a drying zone to dry the droplets exiting the conditioning zone. The conditioning zone comprises humidity control, for example through an humid air inlet, and/or temperature controller to control the conditions in the conditioning zone so that the droplets dry more slowly in the conditioning zone than in the dryer.
According to this disclosure, the drying kinetics may be used to facilitate surface diffusion of surface active components, facilitating amorphous-to-crystalline transformations during the manufacture of dry powder formulations.
In summary, the state-of-the-art only discloses strategies to prevent deposition of product on the walls of the equipment, or the adjustment of powder properties with the introduction of additional solvents or significant changes in atomization and process train configuration.
The inventors of the present invention have appreciated that there is a need for simpler spray drying processes capable of producing materials with higher bulk density, without compromising the process throughput, yield and more important the quality of the product, particularly its amorphous content. In particular, the inventors have appreciated that for spray drying processes for the production of amorphous solid dispersions of active pharmaceutical ingredients and polymers, there is a need to produce spray dried particles with enhanced powder properties such as increased bulk density, lower glass transition temperature and lower residual solvent content. Furthermore, the inventors have appreciated that there is a need to provide spray dried powders with such properties with a simple spray drying process. Although prior art attempts to improve spray dried product properties are known, these processes are complex and typically involve the use of foreign solvents in the drying gas or the introduction of solid material near the atomizer (WO2011/154014 and EP0387950), or the use of controlling drying kinetics with multiple chambers in a spray dryer such as separate conditioning and drying chambers (U.S. Pat. No. 8,337,895). The invention herein disclosed overcomes the shortcomings identified in the prior art.